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Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21(Waf1/Cip1) and p27(kip1)
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-6105-1213
Pomeranian Medical University, Poland.
University of Manitoba, Canada.
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2015 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 13, 2109-2120 p.Article in journal (Refereed) Published
Abstract [en]

Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44(+High)/CD24(-Low) phenotype. This effect was completely reversed in the presence of Akt-specific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21(Waf1/Cip1) and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

Place, publisher, year, edition, pages
Taylor and Francis: STM, Behavioural Science and Public Health Titles , 2015. Vol. 14, no 13, 2109-2120 p.
Keyword [en]
Akt-NLS; cancer stem-like cells; mTOR; PI3K; stemness
National Category
Cell and Molecular Biology
URN: urn:nbn:se:liu:diva-120274DOI: 10.1080/15384101.2015.1041692ISI: 000356959800021PubMedID: 26030190OAI: diva2:843033

Funding Agencies|Linkoping University; Integrative Regenerative Medicine Center (IGEN); VR-NanoVision [K2012-99X-22325-01-5]; Cancerfonden [2013/391]; Canadian Breast Cancer Foundation (CBCF); Natural Sciences and Engineering Research Council of Canada (NSERC); [BK/265/RAU1/2014/t.10]

Available from: 2015-07-24 Created: 2015-07-24 Last updated: 2016-04-27
In thesis
1. PKB/Akt kinase localization and role in stemness maintenance in cancer
Open this publication in new window or tab >>PKB/Akt kinase localization and role in stemness maintenance in cancer
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer incidence rates have increased over the last decade. Currently available therapies are only moderately effective in targeting cancer cells. Established cancer treatment protocols fail to eliminate populations of cancer stem cells (CSCs), which develop resistance against the chemotherapeutic drugs and lead to cancer recurrence. Therefore, understanding the mechanisms by which CSCs resist drugs and identifying molecular markers are both necessary to further improve prognosis and to develop new treatment strategies. Increased protein kinase B/Akt1 gene expression and/or activity have been found increased in majority of cancer types. Akt1 is a key player in PI3K-AktmTOR pathway that is vital for cell survival, proliferation, migration, invasion, metastasis, angiogenesis and apoptosis. In this study, we investigated a series of novel markers to improve the characterization of CSCs, with particular focus the roles of Akt in CSC maintenance and the regulatory role of micro-RNA (miR) in cancer cells. While utilizing in breast cancer cells as models, we found that luminescent conjugated oligothiophenes (LCOs), p-HTMI and p-HTAA have the potential to differentially stain various subpopulations of cancer cells, presumably also CSCs among breast cancer cells. However, further studies are needed to confirm these results. Additionally, when we investigated the effect of Akt intracellular compartmentalization on CSC development, the results revealed that nuclear Akt enhances CSC proliferation (ALDH +/High CD44+/High/CD24-/Low) and clonogenicity, which was counter examined and confirmed by using the Aktspecific inibitor triciribine. Furthermore, while investigating the impact of Akt on miR regulation in cancer cells, we found that Akt overexpression decreased.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 60 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1515
National Category
Cancer and Oncology
urn:nbn:se:liu:diva-127477 (URN)10.3384/diss.diva-127477 (DOI)978-91-7685-806-6 (Print) (ISBN)
Public defence
2016-06-01, Belladonna, Campus US, Linköping, 09:00 (English)
Available from: 2016-04-27 Created: 2016-04-27 Last updated: 2016-04-27Bibliographically approved

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